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Gustav Smith

Associate professor

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Association of FADS1/2 Locus Variants and Polyunsaturated Fatty Acids with Aortic Stenosis

Author

  • Hao Yu Chen
  • Benjamin J. Cairns
  • Aeron M. Small
  • Hannah A. Burr
  • Athithan Ambikkumar
  • Andreas Martinsson
  • Sébastien Thériault
  • Hans Markus Munter
  • Brian Steffen
  • Richard Zhang
  • Rebecca T. Levinson
  • Christian M. Shaffer
  • Jian Rong
  • Emily Sonestedt
  • Line Dufresne
  • Johan Ljungberg
  • Ulf Näslund
  • Bengt Johansson
  • Dilrini K. Ranatunga
  • Rachel A. Whitmer
  • Matthew J. Budoff
  • Albert Nguyen
  • Ramachandran S. Vasan
  • Martin G. Larson
  • William S. Harris
  • Scott M. Damrauer
  • Ken D. Stark
  • S. Matthijs Boekholdt
  • Nicholas J. Wareham
  • Philippe Pibarot
  • Benoit J. Arsenault
  • Patrick Mathieu
  • Vilmundur Gudnason
  • Christopher J. O'Donnell
  • Jerome I. Rotter
  • Michael Y. Tsai
  • Wendy S. Post
  • Robert Clarke
  • Stefan Söderberg
  • Yohan Bossé
  • Quinn S. Wells
  • J. Gustav Smith
  • Daniel J. Rader
  • Mark Lathrop
  • James C. Engert
  • George Thanassoulis

Summary, in English

Importance: Aortic stenosis (AS) has no approved medical treatment. Identifying etiological pathways for AS could identify pharmacological targets. Objective: To identify novel genetic loci and pathways associated with AS. Design, Setting, and Participants: This genome-wide association study used a case-control design to evaluate 44703 participants (3469 cases of AS) of self-reported European ancestry from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort (from January 1, 1996, to December 31, 2015). Replication was performed in 7 other cohorts totaling 256926 participants (5926 cases of AS), with additional analyses performed in 6942 participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Follow-up biomarker analyses with aortic valve calcium (AVC) were also performed. Data were analyzed from May 1, 2017, to December 5, 2019. Exposures: Genetic variants (615643 variants) and polyunsaturated fatty acids (ω-6 and ω-3) measured in blood samples. Main Outcomes and Measures: Aortic stenosis and aortic valve replacement defined by electronic health records, surgical records, or echocardiography and the presence of AVC measured by computed tomography. Results: The mean (SD) age of the 44703 GERA participants was 69.7 (8.4) years, and 22019 (49.3%) were men. The rs174547 variant at the FADS1/2 locus was associated with AS (odds ratio [OR] per C allele, 0.88; 95% CI, 0.83-0.93; P = 3.0 × 10-6), with genome-wide significance after meta-analysis with 7 replication cohorts totaling 312118 individuals (9395 cases of AS) (OR, 0.91; 95% CI, 0.88-0.94; P = 2.5 × 10-8). A consistent association with AVC was also observed (OR, 0.91; 95% CI, 0.83-0.99; P =.03). A higher ratio of arachidonic acid to linoleic acid was associated with AVC (OR per SD of the natural logarithm, 1.19; 95% CI, 1.09-1.30; P = 6.6 × 10-5). In mendelian randomization, increased FADS1 liver expression and arachidonic acid were associated with AS (OR per unit of normalized expression, 1.31 [95% CI, 1.17-1.48; P = 7.4 × 10-6]; OR per 5-percentage point increase in arachidonic acid for AVC, 1.23 [95% CI, 1.01-1.49; P =.04]; OR per 5-percentage point increase in arachidonic acid for AS, 1.08 [95% CI, 1.04-1.13; P = 4.1 × 10-4]). Conclusions and Relevance: Variation at the FADS1/2 locus was associated with AS and AVC. Findings from biomarker measurements and mendelian randomization appear to link ω-6 fatty acid biosynthesis to AS, which may represent a therapeutic target.

Department/s

  • EXODIAB: Excellence of Diabetes Research in Sweden
  • Molecular Epidemiology and Cardiology
  • Cardiology
  • Nutrition Epidemiology
  • EpiHealth: Epidemiology for Health
  • WCMM-Wallenberg Centre for Molecular Medicine

Publishing year

2020

Language

English

Pages

694-702

Publication/Series

JAMA Cardiology

Volume

5

Issue

6

Document type

Journal article

Publisher

American Medical Association

Topic

  • Cardiac and Cardiovascular Systems

Status

Published

Research group

  • Molecular Epidemiology and Cardiology
  • Nutrition Epidemiology

ISBN/ISSN/Other

  • ISSN: 2380-6583